Human erythropoietin (EPO) is a 166-aa glycoprotein which is involved in the proliferation and differentiation of erythroid progenitor cells. These cellular responses are mediated by the human EPO receptor (EPO-R), a 508-aa glycoprotein. Human EPO receptor (EPO-R) is a protein of 508 amino acid length (Swiss Prot P19235) containing a single transmembrane domain and has been classified as a member of the growth hormone subfamily of class I cytokine receptors. EPO-R is e.g. described in Winkelmann, J. C. et al., Blood 76 (1990) 24-30 and Jones, S. S. et al., Blood 76 (1990) 31-35. Activation of EPO-R occurs by dimerization (Matthews, D. J., PNAS 93 (1996) 9471-9476). EPO-R comprises eight cytoplasmic tyrosine sites which become phosphorylated upon stimulation with EPO (Li, K. et al., J. Biol. Chem. 278 (2003) 40702-40709; Wu, H. et al., Proc. Natl. Acad. Sci. USA 94 (1997) 1806-1810) resulting in “activated EPO-R”.
Antibodies against EPO-R are e.g. known from Andrea, A. D., Blood 82 (1993) 46-52; Elliott, S., Blood 107 (2006) 1892-1895; Kirkeby, A., J. Nerosci. 164 (2007) 50-58; Miura, 0., Arch. Biochem. 306 (1993) 200-208; and EP 1 146 056, EP 1 327 681, EP 0 773 962, EP 0 776 370, US 2002/0031806, US 2003/0215444, US 2004/0058393, US 2004/0071694, US 2004/0175379, US 2005/0227289, US 2005/0244409, US 2006/0018902, U.S. Pat. Nos. 6,998,124, 7,053,184, 7,081,523, WO 1995/005469, WO 1996/003438, WO 2000/061637, WO 2004/035603 A2, WO 2005/100403 A2. However it is known form the state of the art, that known antibodies against EPO-R are not able to discriminate between non activated and activated EPO-R (see Jelkmann, W. et al., Crit. Rev. One/Hematol. 67 (2008) 39-61; Li, K. et al., J. Biol. Chem. 278 (2003) 40702-40709, and Wu, H. et al., Proc. Natl. Acad. Sci. USA 94 (1997) 1806-1810).